Dr. Mark Anderson (standing) and Igor Dzhura, Ph.D., examined a protein’s role in arrhythmia. (photo by Dana Johnson)
Enzyme's role in arrhythmia reported
Half of the people who die from heart disease — the number one killer in the United States — die suddenly following an arrhythmia.
Vanderbilt University Medical Center researchers report this month in Nature Cell Biology that an enzyme called CaM kinase might promote arrhythmias and sudden death. Their findings could lead to the development of new anti-arrhythmic drugs.
The research centers on the role of calcium in heart failure and arrhythmias. Calcium plays both good guy and bad guy in the heart. It is important to heart muscle contraction, but it also serves as a source of arrhythmia-generating current, said Dr. Mark E. Anderson, assistant professor of Medicine and Pharmacology.
Calcium enters heart cells through proteins called L-type calcium channels, donut-like pores in the cell membrane that open and close. If these channels stay open and let too much calcium into the cell, the risk of arrhythmia increases.
It was known that calcium itself could signal to keep the channels open, and Anderson and his colleagues suspected that the enzyme CaM kinase, which is activated by calcium, might play a role in telling the channels to stay open. That is exactly what they found.
The investigators measured the opening and closing of single calcium channels using a technique called patch-clamp electrophysiology. Then they added an already-activated form of CaM kinase to the preparation.
"When we added the activated CaM kinase, the calcium channels opened like crazy," Anderson said. "In fact, they were more likely to open and stay open for long periods of time."
"The signaling inside cardiac cells that leads to calcium overload and arrhythmias has been a mystery," said Dr. Jeffrey R. Balser, associate professor of Anesthesiology and Pharmacology and a co-author of the paper. "This work identifies CaM kinase as having a role in that signaling."
Other investigators have demonstrated that CaM kinase is also important for calcium-activated gene expression and that it may be involved in the changes that occur in association with cardiac hypertrophy and heart failure.
"CaM kinase could be the link to explain why calcium channels open more frequently in heart failure, why people in heart failure have arrhythmias, and maybe why heart failure is induced in the first place," Anderson said. "The findings make CaM kinase more desirable as a potential drug target."
Of the existing anti-arrhythmic drugs, only a group known as "beta blockers" have been shown to reduce sudden death in heart disease. "CaM kinase blockers" might offer another option for patients with heart disease, Anderson said.
"Our work supports the idea that CaM kinase is a pro-arrhythmia signaling molecule, so we think it's rational that drugs that block its activity would prevent arrhythmias and sudden death."
Other participants in the research were Igor Dzhura, Ph.D., and Yuejin Wu, Ph.D., both postdoctoral fellows, and Roger J. Colbran, Ph.D., associate professor of Molecular Physiology and Biophysics and a recognized expert on CaM kinase. The work was supported by the National Institutes of Health and the American Heart Association.